I. Field of the Invention
The invention relates generally to the fields of neurology and immunology. Specifically, the invention concerns nucleic acid vaccines for treating and preventing Alzheimer's disease.
II. Description of Related Art
Alzheimer's disease (AD) is the most common cause of dementia, and currently there is no cure or effective treatment to prevent its progression. The cause of AD has been associated with the accumulation, aggregation, and deposition of amyloid beta peptides (Aβ) in cerebral cortex, hippocampus, and other subcortical structures (Selkoe, 2001; Rosenberg, 2000). Aβ is derived proteolytically from a glycosylated membrane protein known as beta-amyloid precursor protein or APP (Haass et al., 1992; Shoji et al., 1992). APP is ubiquitously expressed but is expressed at the highest levels in the central nervous system (Lahiri & Ge, 2004; Fox et al., 1997). The processed Aβ in brain is 39 to 43 amino acids in length with the major species being 40 and 42 amino acids (Aβ40 and Aβ42, respectively). In particular, the aggregated form of Aβ42 has been identified to play a major role in the initiation of neuropathology of AD (Iwatsubo et al., 1994; Iwatsubo et al., 1995; Yankner, 1996).
In recent years, reduction in the level of Aβ in brain has become a major therapeutic goal in prevention and treatment of AD. In transgenic mice carrying mutations causal of AD, reduction of the amyloid burden in brain and cognitive improvement have been achieved by active immunization of these mice with Aβ42 peptide or by infusion of anti-Aβ antibodies (Selkoe, 1999; Monsonego and Weiner, 2003; Schenk et al., 1999; Morgan et al., 2000; DeMattos et al., 2001). These results lead to a clinical trial of patients with Alzheimer's disease that was conducted by active Aβ42 peptide immunization. Unfortunately, the trial was halted due to the complications associated with cytotoxic T lymphocyte (CTL) mediated meningoencephalitis that occurred in about 6% of immunized AD patients (Schenk, 2002; Rosenberg, 2005). Nonetheless, neuropsychological testing of immunized patients showed some slowing of cognitive loss in a subset of patients who exhibited significant anti-Aβ antibody production and subsequent Aβ plaque reduction and clearance upon post-mortem examination (Kotilinek et al., 2002; Hock et al., 2003; Sorbi, 2005; Fox et al., 2005 and Gilman et al., 2005).
A variety of Aβ vaccine strategies have been proposed in the art. For example, U.S. patent publns. 2004/0091945 and 2004/0138296 concern Aβ peptide vaccine compositions for the treatment AD. Peptide Aβ vaccines are also discussed in PCT publication WO 99/27944. However, previous peptide vaccination strategies have resulted in Aβ specific Th1 type immune responses and CTL mediated meningoencephalitis. It has also been suggested that DNA vaccination may be a possible approach to Aβ vaccination U.S. Pat. No. 6,787,140 and PCT publication WO 2005/014041. However, it was not clear how such genetic vaccines might stimulate an improved immune response profile (i.e. a Th2 type response) or what kinds of genetic vaccines would be the most effective. Thus, to date there has not been described an Aβ gene vaccine that can induce a robust Th2 type immune response that results in Aβ plaque reduction.